A Biological Sequence Browser featuring Knowledge Integration

Proceedings of the Virtual Conference on Genomics and Bioinformatics
CATEGORY
Bluejay: A Biological Sequence
Browser featuring Knowledge
Integration
•
Gordon, P.M.K., Stromer, J., Turinsky, A.L.,
Xu, E., Sensen, C.W.1
Post-Genomic Management, Integration and Mining
•
DNA and Amino acid Sequence Comparison
•
Software Application
Keywords: Genome Visualization, Data Integration, Web
Services, BioMOBY, XML, SVG
Sun Center of Excellence for Visual Genomics
University of Calgary
Faculty of Medicine
Department of Biochemistry and Molecular Biology
1. INTRODUCTION
HS1150, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4M1
The amount of data collected by life scientists is growing
at a breathtaking rate. In the last ten years, the number of
genomic sequences submitted to GenBank has been
doubling faster than every two years. Our ability to extract
knowledge from such wealth of data increasingly depends
on the access to sophisticated bioinformatics tools. The
importance of the underlying gene sequence for all types
of bioinformatics analysis cannot be overestimated. A
clear picture of genes’ functions, locations and
interrelations provides a context for the proper analysis of
microarrays, protein-protein interactions and all other data
derived from genes.
Canada
« (403) 210-9543
Correspondence should be addressed to:
csensen@ucalgary.ca
ABSTRACT
Bluejay is a new browser for biological sequences. It offers
users a dynamic and highly customizable display of genomic or
proteomic data, with several levels of visual manipulations. It
serves as a visual front-end unifying the access to distributed
resources, such as bioinformatics data repositories and Web
services. Bluejay imports several data types, combining them
into a coherent visual model. It can also be integrated with other
software tools. The user can interact visually with the whole
sequence, functional categories and individual elements.
Features of Bluejay include semantic zooming, several types of
customizable image granularity, Scalable Vector Graphics
(SVG) imagery, and session management. Bluejay was designed
for ease-of-use by biologists, and maximum availability. It is
available in three versions (http://bluejay.ucalgary.ca/install): 1)
a secure applet, especially suitable for new users who do not
wish to or cannot install software on their machine, 2) Java Web
Start for typical on-line users, and 3) a standalone application
for off-line usage. Bluejay was created to interoperate with
existing software in a broader bioinformatics context through
the extensive use of XML-based standards and protocols.
Bioinformatics has some unique challenges. As a rule, life
scientists are not well trained in computer technology.
Therefore, development of new tools requires balancing
power and ease of use. This has given rise to many visual
data exploration tools. As the analysis of molecular
sequences remains a fundamental problem of
bioinformatics, tools for genome function visualization are
especially important. There is also a growing appreciation
of the complexity of the biological information. System
biology is emerging as a fundamental research direction,
where the ultimate goal is to combine the knowledge of
different biological aspects into a unified model of an
organism.
Based on the Web browser interface model, the Bluejay
browser is intended to deliver some much-needed
innovation in the area of genome function visualization.
Our ultimate goal is to provide the life science community
with a tool for visual data exploration and integration that
is familiar in look-and-feel, while adding functionality that
is both more powerful and novel compared to other
browsers.
Proc Virt Conf Genom and Bioinf (3):4-11
ISSN 1547-383X
Copyright © 2004. All Rights Reserved
www.virtualgenomics.org
Permission to make digital or hard copies of all or part of this work for
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Proceedings of the Virtual Conference on Genomics and Bioinformatics
2. MATERIALS AND METHODS
Input sequence data may be encoded in a number of
formats. Non-XML data, such as FastA flat files, are
converted internally to XML documents. Using XML
internally allows us to use existing Java-based freeware
for parsing, which can be plugged into Bluejay as a set of
separate modules. The logical structure of the document,
in the XML form, serves as a template for accessing,
displaying and manipulating the underlying data. A proofof-concept prototype of Bluejay was previously described
in [1]. Figure 1 presents the flowchart describing the main
data processing steps in Bluejay.
2.1 General Concepts
In this paper we present a biological sequence browser
called Bluejay (Browser for Linear Units in Java). Bluejay
visualizes sequence data, enables visual data queries, and
relates the data to other sources of knowledge. It is
designed as Java client-server software that makes
substantial use of W3C open standards for XML.
Bluejay Proxy Server
XLink
management
XML data
Data
integration
Non-XML data
Translation
into XML
Bluejay Browser
XML SAX parsing into Data DOM
Session
management
XLink management
XPath-enabled legend creation
User activity
data
Abstract painting of visual models
Java2D painting of SVG imagery
BioMOBY services
SVG
interactive
graphics
WSDL-SOAP
processing
USER
Figure 1. Bluejay components and information flow.
2.2 Proxy Server Side
into the data, to relate specific sequence elements to
external sources of knowledge on-the-fly. Bluejay
supports the powerful XLink standard for XML
hyperlinks, which allows such advanced features as
multiple links originating from the same location, links
between third-party data, and persistent link libraries
(linkbases). The Bluejay proxy server also performs
session management. Users can create and manage
projects, logon to a previous work session from a different
computer, or switch between several simultaneous work
sessions. Future improvement of the session management,
such as an upcoming engine for content personalization,
will also be handled at the proxy side.
The proxy server establishes the communication between
the Bluejay browser side and the sources of biological
content: data, websites and data analysis services. This
includes retrieval of remote data requested by the user,
data preprocessing, delivery of the data to the Bluejay
browser side for visualization, and session management.
The need for a proxy originated with applet security
restrictions, but has persisted mainly because of applet
memory limitations and the potential benefits of
centralized knowledge for “intelligently” managing a
user’s browsing experience. The proxy and client have
been designed to not be codependent - if no Internet
connection is available, the client application will still run,
with a limited loss of functionality.
2.3 Client Side
Data preprocessing may involve several aspects:
translation into XML, insertion of XLinks, and
personalization. A part of the proxy server is a data
translator that translates flat files and other non-XML
data into XML before passing the information to the
browser. The proxy may also insert additional hyperlinks
The browser side receives and visualizes the incoming
XML data. It also offers the user a range of visual tools to
query the data, customize its appearance, and save the
results. The client is generally patterned after a Web
browser interface, with a location bar, side tabs, and back
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Proceedings of the Virtual Conference on Genomics and Bioinformatics
have found that many of the biological XML files achieve
five-fold or better compression using the ubiquitous gzip
compression utility. Skeletonization involves the
transformation of a large document into a pared-down
version via an XML transformation stylesheet. The data
removed generally contain very detailed information not
required for the initial high-level rendering of the
document, but when the user “drills-down” into the image
(i.e. displays a fraction of the whole molecule in detail).
The stubs for these detailed data are represented by
embedded XLinks. Skeletonization is an experimental
feature in Bluejay, requiring the on-demand brokering of
requests for detailed information as a user drills down into
a large document such as a eukaryotic chromosome.
Together these two techniques can make unwieldy data
browsing manageable; for the TIGR Arabidopsis thaliana
chromosome 2 annotation, the original document size of
30.5MB was reduced to 2.9MB with skeletonization,
3.2MB with compression, and 244KB with both methods
used in combination.
and forward buttons to aid in the navigation between
XML resources. Non-XML resources that are not
translatable by the proxy are delegated for viewing to the
user’s default Web browser. The client communicates
with the proxy over the Web using SOAP [2]. The
incoming XML data is parsed into an internal DOM tree
[3], where nodes represent nested XML tags. Relevant
XLinks, including third-party links, are identified and
registered. The visual model is then created as a collection
of backbone sequences, such as DNA or protein
backbones, with respect to which all other visual elements
are placed.
Bluejay painting logically separates high-level placement
of elements onto a sequence from low-level rendering of
images onto a canvas. High-level painting of an element
(e.g. a gene) is performed by specifying its positions on a
target sequence (e.g. a DNA molecule). Note that
sequence positions are intrinsic to the data and remain
constant as the user manipulates the visual model. At a
lower level, the Java object representing the target
sequence translates positions of sequence features into
canvas coordinates and calls the respective Java
Graphics2D class. This separation into high-level and
low-level painting makes Bluejay architecture more robust
and easily extendable to new data types.
2.4.2. CPU limitations
CPU bottlenecks tends to occur during data analysis (such
as sequence alignments) and redrawing after layout or
position changes. The former is dealt with by farming out
analysis to Web services, while the latter is dealt with by
using an efficient ‘windowing’ mechanism. Because the
position of features does not change while browsing a
document, an index is constructed on document load and
constantly reused to only call the paint function for
elements which should be visible on the screen. This is
important when you consider that a eukaryotic
chromosome may have hundreds of thousands of painted
elements.
The Bluejay graphics is based on the Scalable Vector
Graphics (SVG), a cross-disciplinary XML standard for
imagery. The Java Graphics2D object for low-level
painting is adapted to create SVG tags. The resulting SVG
document is an explicit and portable XML representation
of the visual model. An SVG-enabled canvas visualizes
this model and allows the user to interact with it. Bluejay
translates these visual interactions into actions on the
original sequence data. To implement SVG, we used the
open-source Apache SVG browser Batik [4], plugging it
into the Bluejay main browser and connecting it to the
data DOM tree. Data access is based on XPointer and
XPath standards for DOM [5].
2.4.3 Memory limitations
Applets are restricted to 64MB of memory, making the
viewing of very large documents impossible. For bacteriasized genomes, applet users can take advantage of the
“memory-saving” mode of Bluejay, which does not keep
the DOM in memory during browsing, but reloads the
document from a local disk cache when required. For
users with Java 1.3 and above, the Web Start option gives
them a one-click launch solution without the memory
restriction.
2.4 Dealing with Large Data Sets
Bluejay employs several techniques to overcome
bandwidth, CPU and memory limitations associated with
manipulating genome-scale data.
3. RESULTS
2.4.1. Bandwidth limitations
3.1 Bluejay gives control to the user
Two techniques are used to minimize network traffic:
compression and skeletonization. The Bluejay client will
decompress zipped files in the case that the incoming
document was a zipped file or just zip-encoded for
transport efficiency by the originating Web server. We
Bluejay can visualize biological sequences ranging from
simple bacterial genomes to complex eukaryotic genomes.
It currently provides a fully customizable view of the
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Proceedings of the Virtual Conference on Genomics and Bioinformatics
By setting the level of nesting in the context tree, the user
can customize the desired level of refinement.
various sequence features: genes, introns and exons,
repeat regions, markers, promoter and terminator sites,
G+C% and A+G% content plots, as well as various Gene
Ontology classes [7]. Bluejay supports several common
data formats: TIGR XML, GenBank XML, FastA,
BioML, BSML, Agave XML - which enables it to handle
the majority of existing genomic sequence data. Figure 2
shows a sample Bluejay interface.
Bluejay allows the user to perform visual data
explorations in several scopes. First, sequence-wide
operations include switching between linear and circular
models of the sequence (important for visualizing
bacterial genomes), switching between normal and
reverse-complement views of a double-stranded sequence,
rotation by a desired angle, and “ cutting” at a specified
start position, e.g. at the beginning of a gene. Second, an
interactive legend enables operations on specific
functional categories. For example, the user may click on
the legend item “ Enzymes” and either ghost out or
completely remove all enzyme-producing genes from the
visual model of a DNA. By setting the level of details in
the context tree, the granularity of the legend can be
adjusted, from a longer list of narrow functional
categories, e.g. various types of enzymes, to a shorter list
of broad categories. Third, the user can access any
individual element on the sequence through mouse clicks.
For example, by clicking on an image of a gene, the user
can access that gene’ s data and XLinks, and thus be able
to request a gene annotation web page or relevant Webbased analysis services (see below).
A key benefit of using Bluejay is the ability to save the
image in the SVG format. Unlike pixel-based image
format (JPEG, GIF, etc.), SVG allows an image to retain
its full quality regardless of the scale. The saved image
can then be resized to any resolution, from small images
for journal articles to large posters. A wall-size poster
image of a complete genome will retain its finest details in
SVG format. SVG images can also be edited by any SVGcompliant visual editor (e.g. Corel Draw).
Figure 2. Bluejay displaying the E. coli K12 genome
With Bluejay, the user has a wide range of options to
customize the visual display, adjust the level of detail, and
perform visual operations on the sequence data. The user
can also save the customized visual model in a scalable
publication-quality format.
There are three main ways to customize the level of detail.
First, Bluejay provides several view modes, such as a piechart summary of sequence features, a graphical view of
the sequence, an expanded graphical view with all six
open reading frames shown, and a textual view of the
sequence as a string of characters. All views are colorcoded consistently according to feature types and
functional categories as defined in the legend. Secondly,
Bluejay provides a semantic zoom, which shows new,
finer features of the data at a higher resolution [6]. The
zooming range in Bluejay is virtually unlimited. Third, the
granularity can be adjusted through the context tree, a
visual tool in the main browser window that contains a
semantic hierarchy of the XML data elements. Nesting of
XML elements often represents a semantic refinement,
such as a Gene Ontology hierarchy of terms [7] or
additional XML tags with sequence annotation details.
3.2 Bluejay is made easy to use for biologists
The success of bioinformatics software depends critically
on its user friendliness. Life scientists are much less likely
to use software that requires an above-basic degree of
computer expertise. Bluejay provides the ease-of-use
through several aspects: ease of access, comfortable
interaction, and session management.
Bluejay can be accessed in three versions: as a web applet,
one-click Web Start or a downloadable application
(http://bluejay.ucalgary.ca/install). For first time users, a
web applet is the ideal environment to get familiar with
the tool. Bluejay provides a VeriSign-certified secure
applet [8], which allows users to save files locally or
upload local data into the applet. If a complex task
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Proceedings of the Virtual Conference on Genomics and Bioinformatics
annotation information provided by MAGPIE, both visual
and textual. XLinks can lead to other desired sources,
such as organism-specific databases, NCBI web resources,
and PubMed article citations. Bluejay thus serves as a
visual front-end to a distributed collection of
bioinformatics resources and tools.
requires large memory resources, the user may use Web
Start or download a platform-independent application
version. The only requirement is to have a current version
of Java Virtual Machine (JVM) on the user’ s system,
which is commonly available (http://java.sun.com). If
Java is not installed, the Bluejay download website
provides a link to download both the JVM and Bluejay in
a single click. Java enjoys widespread name recognition
among biologists, which further reduces the psychological
resistance to use Bluejay.
Conversely, other bioinformatics tools can launch a
Bluejay browser. For example, icon hyperlinks launching
a Bluejay applet for each genome are already available
from the MAGPIE Web site. They are enabled by a small
JavaScript, which simply brings up a Bluejay applet web
page, passing it the name of a genome data file associated
with the clicked icon. Users of MAGPIE who explore the
static sequence annotation pages can thus launch a
dynamic browser to explore any of nearly a hundred
genomes using the “ Bluejay” icon links available on the
main genome listings pages.
All interaction with the browser is performed through the
GUI. No programming, scripting, or command line
parameters are required to configure the browser or to
analyze the data. This makes work with Bluejay highly
intuitive, eliminates any requirements on user expertise,
and shortens the learning curve. The Bluejay Help menu
contains a step-by-step explanation of the navigation
process and main features.
Session management further improves usability. Bluejay
can recognize the user and resume a previously
interrupted investigation, possibly from a different
computer. We shall soon implement a personalization
engine to be able to prioritize the content (e.g. data
sources and Web services) according to individual
preferences. Session management is optional and users
may still work with Bluejay anonymously.
3.3 Bluejay is a knowledge integration tool
Meaningful data integration is among the most important
technical tasks in the area of bioinformatics. While
powerful methods have been developed to analyze various
types of data separately, the emerging grand challenge for
biology is to combine these analyses into a coherent
model of an organism. Bluejay development aims at
creating a data exploration tool that can interoperate with
other tools and integrate heterogeneous biological
information into its visual model.
Users can access other tools and data resources from
Bluejay. This functionality is enabled by an extensive
support for XLinks. For example, graphically-rich
MAGPIE
gene
annotation
pages
[9]
(http://magpie.ucalgary.ca) can be launched by clicking on
gene representations in Bluejay. MAGPIE currently hosts
90 publicly available genomes and uses powerful
sequence analysis accelerators, such as Paracel
GeneMatcher2 [10] and TimeLogic DeCypher [11] to
produce comprehensive annotations of these genomes.
Through XLink insertion and management, Bluejay
relates sequence visualization to a wealth of functional
Figure 3. A portion of the Sulfolobus solfataricus genome with
oligonucleotides embedded into the visual model. The view also
shows repeats (green), and both G+C% (black) and A+G% (red)
composition.
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Proceedings of the Virtual Conference on Genomics and Bioinformatics
4. DISCUSSION
Bluejay can combine data from different sources into a
meaningful visual model. To date, we have successfully
integrated genomic sequence annotations from MAGPIE
with oligonucleotide primer computations by Osprey [12].
The combined display (Figure 3) is a helpful visual guide
for the production of DNA microarray chips. Our current
work is on integrating microarray gene expression data
into the Bluejay visualization. As a result, researchers
using Bluejay will be able to inspect regions of an
organism’s genome that are active, and better comprehend
genome-wide patterns of protein production and metabolic
pathways. Other data types that we plan to integrate in the
future include protein modification and protein-protein
interaction data.
To meet the growing demand for bioinformatics tools, a
number of biological sequence browsers have already
been developed. Currently, the most advanced generalpurpose browsers include Ensembl Genome Browser [14],
NCBI Map Viewer [15], TIGR Comprehensive Microbal
Resource [16], and UCSC Genome Browser [17]. These
tools deliver their content as dynamically generated web
forms and image maps. Other, less well known tools exist
that are based on the same principle. The advantage of
using these browsers lies in their immediate access to a
wealth of information at each facility. In contrast, Bluejay
must explicitly relate its data to other knowledge sources
through XLinks. However, compared to Bluejay, these
browsers have five main limitations.
3.4 Bluejay facilitates biology Web Services
BioMOBY [13] is a protocol consisting of a common
XML object ontology for biological entities, and a
standardized request/response mechanism for performing
analysis of the Web on these objects. Bluejay is the first
Java-based BioMOBY client. Bluejay contains semantic
mapping between its supported XML formats and the
BioMOBY object ontology, allowing the user to directly
link from the visually presented data to BioMOBY
compliant Web services. Invoking Web-based analysis of
the source data simply involves clicking on its Bluejay
visual representation, and selecting options from the
resulting pop-up menu. Results are displayed in HTML
format in a separate window, and can be used to requery
BioMOBY, thus forming analysis chains. As BioMOBY
services grow in number and diversity we see a clear
opportunity to use information gleaned by the proxy to
help facilitate service selection.
First, the user has far less control over the sequence
appearance. Of the browsers listed above, only the
Ensembl browser offers a comparable range of options for
customizing the display. Second, the user is forced to
communicate with a remote web server for every
interaction, which brings up several technical issues such
as limitations of bandwidth or availability of a stable
Internet connection. Unlike Bluejay, there are no
downloadable application versions available. Most of the
other major tools were created primarily to showcase the
genomic information accumulated at a principal facility
(EBI/Sanger, NCBI, TIGR and UCSC). None is,
therefore, primarily designed to import additional data for
visualization or interoperate with other resources. Fourth,
these tools can only export pixel-based images, which,
unlike SVG images, lose their quality after resizing.
Finally, these browsers do not currently offer any session
management or personalization.
Several sequence browsers exist in the form of applets and
downloadable applications, e.g. the Vista Genome
Browser [18] and the Apollo Genome Annotation Tool
[19]. While allowing an easy web access, applets
eliminate the need to communicate with a remote web
server for each interaction and typically offer more
options for manipulating the data. However, unlike the
VeriSign-certified Bluejay applet, existing genome
browser applets are not secure and, therefore, cannot save
or read data files locally. This is a major limitation.
Currently, we are not aware of any secure applet tool
other than Bluejay for browsing biological sequences.
Figure 4. Interface for BioMOBY Web services activated by
clicking on the graphical representation of a gene, with service
options in cascading popup menus. Menu items have fly-over
"tool tips". The results of a service are displayed in a separate
window, shown here in the upper left hand corner.
New genomic browsers with advanced features are being
created, such as Gbrowse and Sockeye. Gbrowse [20] is
designed as a front end to a Generic Model Organism
System Database Project (GMOD). Like Bluejay, it is a
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Proceedings of the Virtual Conference on Genomics and Bioinformatics
Given the clear importance of gene function context for
all sorts of bioinformatics analysis, we see great potential
for sequence visualization and visual analysis. The
growing influence of bioinformatics on other areas of
biology is a trend that will continue for the forseeable
future. This will require new, more powerful, more
versatile tools for data analysis and knowledge
integration. The dynamic sequence browser presented in
this work is a next step in this important direction.
component-based tool that supports BioMOBY services
and can be installed as a front end to other data sources.
However, Bluejay differs from Gbrowse in several ways.
Bluejay is designed to visualize a variety of data types,
whereas Gbrowse focuses on comparison of sequence
annotations. The Bluejay client itself does not include
database components and is purely a front-end
visualization tool. The Bluejay interface is not hypertextbased and therefore is not subject to the associated
limitations
such
as
static
images,
browser
incompatibilities, and constant round-trips to the remote
server for display changes. Bluejay uses components
based on interdisciplinary standards that are not a part of
Bluejay project, which makes its modular architecture
more generic.
6. ACKNOWLEDGMENTS
The Sun Center of Excellence for Visual Genomics
projects are funded by ANPI, the Alberta Network for
Proteomics Innovation; ASRA, the Alberta Science and
Research
Authority;
WD,
Western
Economic
Diversification; CFI, the Canadian Foundation for
Innovation; Genome Canada; Genome Prairie; NSERC,
the National Sciences and Engineering Council; Sun
Microsystems Inc.; Fakespace Systems Inc.; and the
University of Calgary. We would also like to acknowledge
the code contributions made by Praveen Agrawal, Andrew
Ah-Seng, Jeroen Keijser, and Morgan Taschuk.
Another example of recent advances is the Sockeye
browser [21]. Sockeye is the core data viewer of the
Bioinformatics of Mammalian Gene Expression project. It
is a downloadable Java 3D application that can also be
launched using Java Web Start. Key Sockeye features
include 3D visualization of genomic sequences and their
alignments and support of Ensembl data. However, unlike
Bluejay, Sockeye offers considerably less functionality for
XML open standards and XML technology, such as XML
hyperlinks, XML data manipulation, or SVG graphics.
While Sockeye can visualize external data such as GFF or
Ensembl data, its interoperation with a wide range of other
bioinformatics tools has not been a priority in the Sockeye
design.
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platform-independent Java software tool available both as
a secure web applet and as a downloadable application.
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biological sequences, with a wide range of options for
customizing the visual model and querying the data. It
creates publication-quality scalable images of the data,
offers session management options, and is designed to
interoperate with other bioinformatics tools.
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Proceedings of the Virtual Conference on Genomics and Bioinformatics
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